The present invention relates to new benzhydryl derivatives and a salt thereof.
More particularly, it relates to new benzhydryl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
Accordingly, one object of the present invention is to provide new and useful benzhydryl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
Another object of the present invention is to provide a process for the preparation of said benzhydryl derivatives and a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said benzhydryl derivatives and a pharmaceutically acceptable salt thereof.
Still further object of the present invention is to provide a use of said benzhydryl derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, couph, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.
The object compound of the present invention can be represented by the following general formula (I): 
in which R1 and R2 are independently hydrogen, halogen, lower alkoxy, lower alkyl or mono(or di or tri)halo(lower)alkyl,
R10 is hydrogen or lower alkyl optionally substituted with lower alkoxy, carbamoyl or phenyl,
R11, R12, R13 and R14 are independently hydrogen, lower alkoxycarbonyl or lower alkyl optionally substituted with hydroxy or lower alkoxy, and
R10 and R14 optionally forming xe2x80x94(CH2)ixe2x80x94CHR15xe2x80x94(CH2)jxe2x80x94, xe2x80x94(CH2)ixe2x80x94NR16xe2x80x94(CH2)jxe2x80x94, xe2x80x94(CH2)ixe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94 or xe2x80x94(CH2)ixe2x80x94Oxe2x80x94(CH2)jxe2x80x94, wherein i and j are independently 1 or 2, R15 is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino or di(lower)alkylamino and R16 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, benzyloxycarbonyl, lower alkylsulfonyl or mono(or di or tri)halo(lower)alkylsulfonyl, or
R12 and R13 optionally forming xe2x80x94(CH2)ixe2x80x94CHR15xe2x80x94(CH2)jxe2x80x94, wherein i, j and R15 are defined as above, or
R13 and R14 optionally forming oxo or two to five methylenes, 
in which R3, R4 and R5 are independently hydrogen; halogen; lower alkyl; mono(or di or tri)halo(lower)alkyl; cyano; lower alkoxycarbonyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy optionally substituted with lower alkoxy, lower alkoxycarbonyl, carbamoyl, cyano, phenyl or one, two or three halogen(s); lower alkenyloxy; cyclo(lower)alkyloxy; nitro; lower alkylamino; di(lower)alkylamino; or imidazolyl, pyrazolyl, thienyl, thiazolyl, furyl, tetrazolyl, pyridyl or phenyl, each of which may have a substituent selected from a group which consists of lower alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkylamino and di(lower)alkylamino, and
R6 and R7 are independently hydrogen or halogen, and
R8 is hydrogen or lower alkyl.
It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention
It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes. 
wherein
Z, R1, R2, R8 and R16 are each as defined above, and
W1 is a leaving group.
As to the starting compounds (II) and (III), some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or similar manners thereto.
Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.), or the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise indicated.
Suitable xe2x80x9chalogenxe2x80x9d and xe2x80x9chalogenxe2x80x9d moiety in the terms xe2x80x9cmono(or di or tri)halo(lower)alkylxe2x80x9d, xe2x80x9cmono(or di or tri)halo(C1-C4)alkylxe2x80x9d, etc. may include fluorine, chlorine, bromine and iodine.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d moiety in the terms xe2x80x9cmono(or di or tri)halo(lower)alkylxe2x80x9d, xe2x80x9clower alkylaminoxe2x80x9d, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like, in which the preferred one is C1-C4 alkyl and the most preferred one is methyl, ethyl or isopropyl.
Suitable xe2x80x9cmono(or di or tri)halo(lower)alkylxe2x80x9d and xe2x80x9cmono(or di or tri)halo(lower)alkylxe2x80x9d moiety in the term xe2x80x9cmono(or di or tri)halo(lower)alkylsulfonylxe2x80x9d may include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2-bromoethyl, 1 or 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d and xe2x80x9ccyclo(lower)alkylxe2x80x9d moiety in the term xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Suitable xe2x80x9clower alkenylxe2x80x9d moiety in the term xe2x80x9clower alkenyloxyxe2x80x9d may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)-butenyl, and the like, in which more preferable example may be C2-C4 alkenyl.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d moiety in the terms xe2x80x9clower alkoxycarbonylxe2x80x9d, etc. may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one is C1-C4 alkoxy and the most preferred one is methoxy.
Suitable xe2x80x9clower alkanoylxe2x80x9d may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the like.
Suitable xe2x80x9cleaving groupxe2x80x9d may include lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.), aryloxy (e.g., phenoxy, naphthoxy, etc.), an acid residue or the like.
Suitable xe2x80x9cacid residuexe2x80x9d may be halogen (e.g., chlorine, bromine, iodine, etc.), sulfonyloxy (e.g., methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.
Preferred embodiments of the object compound (I) are as follows: 
in which R1 and R2 are independently hydrogen, C1-C4 alkoxy, C1-C4 alkyl or mono(or di or tri)halo(C1-C4)alkyl,
R10 is hydrogen or C1-C4 alkyl (more preferably methyl) optionally substituted with C1-C4 alkoxy, carbamoyl or phenyl,
R11 and R13 are independently hydrogen, C1-C4 alkoxycarbonyl (more preferably methylcarbonyl) or C1-C4 alkyl optionally substituted with hydroxy or C1-C4 alkoxy (more preferably hydroxymethyl),
R16 is hydrogen, C1-C4 alkyl (more preferably methyl), C1-C4 alkanoyl (more preferably acetyl), C1-C4 alkoxycarbonyl (more preferably methoxycarbonyl), benzyloxycarbonyl, C1-C4 alkylsulfonyl or mono(or di or tri)halo(C1-C4)alkylsulfonyl, 
in which R3, R4 and R5 are independently hydrogen; halogen (more preferably fluorine, chlorine or bromine); C1-C4 alkyl (more preferably methyl); mono(or di or tri)halo(C1-C4)alkyl (more preferably trifluoromethyl); cyano; C1-C4 alkoxycarbonyl (more preferably methoxycarbonyl); C1-C4 alkylthio (more preferably methylthio); C1-C4 alkylsulfonyl (more preferably mesyl); hydroxy; C1-C4 alkoxy (more preferably methoxy, ethoxy, propoxy or isopropoxy) optionally substituted with C1-C4 alkoxy (more preferably methoxy), C1-C4 alkoxycarbonyl (more preferably methoxycarbonyl), carbamoyl, cyano, phenyl or one, two or three halogen(s) (more preferably fluorine); C2-C4 alkenyloxy (more preferably 2-propenyloxy); cyclo(C3-C6)alkyloxy (more preferably cyclopentyloxy); nitro; C1-C4 alkylamino (more preferably methylamino); di(C1-C4)alkylamino (more preferably dimethylamino); or imidazolyl, pyrazolyl, thienyl, thiazolyl, furyl, tetrazolyl, pyridyl or phenyl, each of which may have a substituent selected from a group which consists of
C1-C4 alkyl (more preferably methyl), mono(or di or tri)halo(C1-C4)alkyl (more preferably trifluoromethyl), C1-C4 alkylsulfonyl (more preferably methylsulfonyl), C1-C4 alkylsulfinyl (more preferably methylsulfinyl), C1-C4 alkylthio (more preferably methylthio), C1-C4 alkylamino (more preferably methylamino) and di(C1-C4)alkylamino (more preferably dimethylamino), and
R6 and R7 are independently hydrogen or halogen, and
R8 is hydrogen or C1-C4 alkyl.
More preferred embodiments of the object compound (I) are as follows: 
in which R1 and R2 are independently hydrogen, C1-C4 alkoxy, C1-C4 alkyl or mono(or di or tri)halo(C1-C4)alkyl, and
R16 is hydrogen, C1-C4 alkyl (more preferably methyl), C1-C4 alkanoyl (more preferably acetyl), C1-C4 alkoxycarbonyl (more preferably methoxycarbonyl), benzyloxycarbonyl, C1-C4 alkylsulfonyl or mono(or di or tri)halo(C1-C4)alkylsulfonyl, 
in which R3 is hydrogen,
R4 is C1-C4 alkoxy (more preferably methoxy), and
R5 is imidazolyl, pyrazolyl, thienyl, thiazolyl, furyl, tetrazolyl, pyridyl or phenyl, each of which may have a substituent selected from a group which consists of
C1-C4 alkyl (more preferably methyl), mono(or di or tri)halo(C1-C4)alkyl (more preferably trifluoromethyl), C1-C4 alkylsulfonyl (more preferably methylsulfonyl), C1-C4 alkylsulfinyl (more preferably methylsulfinyl), C1-C4 alkylthio (more preferably methylthio), C1-C4 alkylamino (more preferably methylamino) and di(C1-C4)alkylamino (more preferably dimethylamino), and
R8 is hydrogen or C1-C4 alkyl.
The Processes 1 and 2 for preparing the object compound (I) of the present invention are explained in detail in the following.
Process 1
The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the imino group or a salt thereof with the compound (III) or a salt thereof.
Suitable reactive derivative at the imino group of the compound (II) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
The reaction may also be carried out in the presence of a reductive regent such as hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process 2
The object compound (Ib) or a salt thereof can be prepared by reacting the compound (Ia) or a salt thereof with the compound (IV) or a salt thereof.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonate (e.g. potassium carbonate, etc.), alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkyl-morpholine, N,N-di(lower)alkylethylamine (e.g. N,N-diisopropylethylamine, etc.), N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The object compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykinin-mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis (e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g. migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.); and the like.
Further, it is expected that the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like;
gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud""s disease, and the like;
epilepsy; spastic paralysis; pollakiuria; cystitis; bladder detrusor hyperreflexia; urinary incontinence; Parkinson diseases; dimentia; AIDS related dementia; Alzheimer""s diseases; Down""s syndrome; Huntington""s chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-positive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and the like.
It is furthermore expected that the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; iritis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn""s diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; telalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis (e.g., nausea, retching, vomiting, acute emesis, delayed emesis, anticipatory emesis, past operative nausea and vomiting (PONV), acute and/or delayed emesis induced by drugs such as cancer chemotherapeutic agents, etc.); mental diseases, particularly anxiety disorders, stress-related disorders, affective disorders, psychological development disorders and schizophrenia; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis; attenuation of morphine withdrawal; oedema, such as oedema caused by thermal injury; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as poison ivy; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; reflex sympathetic dystrophy such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress related somatic disorders; rheumatic diseases such as fibrositis; aggressive behaviour, optionally taking an antipsychotic agent together; mania or hypomania, optionally taking an antipsychotic agent together; symptoms associated with Premenstrual Syndrome (PMS) (PMS is also now referred to as Late Luteal Phase Syndrome (LLS); psychosomatic disoredrs; psychoimmunologic disoredrs; attetion deficit disoredrs (ADD) with or without hyperactivity; and the like.
Furthermore, the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System (CNS) penetrant.
For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enternal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration. The pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the compound (I) will vary depending upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating Tachykinin-mediated diseases such as asthma and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
In order to show the utility of the object compound (I) and a pharmaceutically acceptable salt thereof, the pharmacological test data of some representative compounds of the present invention is shown in the following.
Emesis in the Dog
[I] Test Method
Individually housed adult female dogs (8 to 15 kg) were given an i.v. injection of a solution containing a test compound. 5 Min later the emetic responses (retching and vomiting) were induced by administration of subcutaneous apomorphine (0.1 mg/0.5 ml/kg) and observed for the next 60 min. The timing and number of retches and vomits observed were recorded for each animal. An individual animal was tested with at least 10 days between experiments.
[II] Test Result
The following Test Compound showed 90% inhibition rate of emesis in the dog at the dose of 1.0 mg/kg.
Test compound: The object compound of the Example 28
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) (77 ml) was added portionwise to a stirred solution of 1,4-dibenzyl-2,5-piperazinedione (20.6 g) in a mixture of tetrahydrofuran (400 ml) and N,N-dimethylformamide (200 ml) at 0xc2x0 C. The whole was stirred at 5xc2x0 C. for 1 hour and thereto a solution of bromodiphenylmethane (19 g) in tetrahydrofuran (100 ml) was added at xe2x88x9278xc2x0 C. and the mixture was stirred for 2 hours at the same temperature. After being stirred at 5xc2x0 C. for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixed solvent of ethyl acetate and isopropyl alcohol, and the resulting solid was collected by filtration to give 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione (10.55 g) as a colorless powder.
NMR (DMSO-d6, xcex4): 3.27 (1H, d, J=13.0 Hz), 3.71 (1H, d, J=17.4 Hz), 3.84 (1H, d, J=17.4 Hz), 4.23 (1H, d, J=14.6 Hz), 4.49-4.81 (4H, m), 7.03-7.54 (20H, m)
MASS (APCI): 461 (M+H)+
Preparation 2
The following compound was obtained according to a similar manner to that of Example 4.
4-tert-Butoxycarbonyl-2-benzhydryl-1-methylpiperazine
NMR (DMSO-d6, xcex4): 1.10-1.45 (9H, m), 1.21 (3H, s), 2.40-3.50 (6H, m), 4.05-4.25 (1H, m), 7.10-7.43 (10H, m)
MASS (APCI): 367 (M+H)+
Preparation 3
4N Hydrogen chloride in 1,4-dioxane (44 ml) was added to a solution of 4-tert-butoxycarbonyl-2-benzhydryl-1-methylpiperazine (6.5 g) in ethanol (33 ml) under ice-cooling over 30 minutes. The mixture was stirred at room temperature for 4 hours and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and the resulting solid was collected by filtration to give 2-benzhydrylpiperazine dihydrochloride (6.02 g) as a powder.
NMR (DMSO-d6, xcex4): 2.50-3.95 (6H, m), 3.56 (3H, s), 4.30-5.50 (2H, m), 7.21-7.57 (11H, m)
MASS (APCI): 267 (M+H)+ (free)
Preparation 4
A solution of 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione dihydrochloride (840 mg) in methanol (10 ml) was hydrogenated over 10% palladium-carbon (50% wet, 84 mg) at room temperature under atmospheric pressure for 5 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give an oil, which was treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydrylpiperazine dihydrochloride (525 mg) as a colorless powder.
NMR (DMSO-d6, xcex4): 3.12-3.89 (8H, m), 4.39 (1H, d, J=11.1 Hz), 4.59 (1H, m), 7.26-7.49 (10H, m)
MASS (APCI): 253 (M+H)+ (free)
Preparation 5
The following compounds were obtained according to a similar manner to that of Preparation 4.
(1) 6-Benzhydrylpiperazine-2-one
NMR (DMSO-d6, xcex4): 2.43-2.75 (3H, m), 3.19 (2H, s), 4.14 (2H, m), 6.43 (1H, br s), 7.14-7.45 (10H, m)
MASS (APCI): 267 (M+H)+
(2) 5-Benzhydryl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine dihydrochloride
MASS (APCT): 290 (M+H)+ (free)
(3) (2S)-2-Benzhydrylpiperazine dihydrochloride
NMR (DMSO-d6, xcex4): 3.12-3.89 (8H, m), 4.39 (1H, d, J=11.1 Hz), 4.59 (1H, m), 7.26-7.49 (10H, m)
MASS (APCI): 253 (M+H)+ (free)
(4) (2S)-2-Benzhydryl-1-methylpiperazine dihydrochloride
NMR (DMSO-d6, xcex4): 2.66-4.89 (12H, m), 7.21-7.56 (10H, m)
MASS (APCI): 267 (M+H)+ (free)
(5) (2R)-2-Benzhydryl-1-methylpiperazine dihydrochloride
NMR (DMSO-d6, xcex4): 2.66-4.89 (12H, m), 7.21-7.56 (10H, m)
MASS (APCI): 267 (M+H)+ (free)
(6) (2R)-2-Benzhydrylpiperazine dihydrochloride
NMR (DMSO-d6, xcex4): 3.12-3.89 (8H, m), 4.39 (1H, d, J=11.1 Hz), 4.59 (1H, m), 7.26-7.49 (10H, m)
MASS (APCI): 253 (M+H)+ (free)
Preparation 6
Di-tert-butyl carbonate (996 mg) was added to a mixture of 2-benzhydrylpiperazine dihydrochloride (1.65 g) and N,N-diisopropylethylamine (3.5 ml) in N,N-dimethylformamide (17 ml) under ice-cooling. After being stirred at same temperature for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (50:1) to give 1-tert-butoxycarbonyl-3-benzhydrylpiperazine (1.26 g) as a colorless powder.
NMR (CDCl3, xcex4): 1.39 (9H, s), 2.63-2.95 (4H, m), 3.34 (1H, m), 3.74-3.95 (3H, m), 7.17-7.39 (10H, m)
MASS (APCI): 353 (M+H)+
Preparation 7
A solution of 2-benzhydryloxirane (631 mg) in isopropyl alcohol (4 ml) was added portionwise to a stirred solution of 2-aminoethyl hydrogensulfate (2.12 g) in a mixture of 20% sodium hydroxide solution (3 ml) at 50xc2x0 C. The whole was stirred at 100xc2x0 C. for 6 hours and thereto 40% sodium hydroxide solution (6 ml) was added at 100xc2x0 C. After being stirred for 18 hours at the same temperature, the mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1) to give 2-benzhydrylmorpholine (102 mg) as a colorless powder.
NMR (CDCl3, xcex4): 2.50-2.92 (4H, m), 3.63 (1H, m), 3.84 (1H, m), 3.92 (1H, d, J=9.6 Hz), 4.20 (1H, ddd, J=9.6, 9.6, 2.5 Hz), 7.14-7.37 (10H, m)
MASS (APCI): 254 (M+H)+
Preparation 8
Lithium aluminum hydride (114 mg) was added by small portions to an ice-cooled solution of 1-benzhydryl-2-(N-methoxymethylamino)-2-oxoethylcarbamic acid tert-butyl ester (1.15 g) in tetrahydrofuran (10 ml) below 5xc2x0 C. under nitrogen atmosphere. After the mixture was stirred at the same temperature for 1 hour, 2N sodium hydroxide (0.5 ml) was added to the mixture. After the mixture was stirred for 30 minutes, the insoluble materials were removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were combined, and evaporated under reduced pressure. The residue was dissolved into dichloromethane (15 ml), and N-benzylglycine ethyl ester (609 mg) was added to the solution. To the resulting solution sodium triacetoxyborohydride (1.27 g) was added portionwise under stirring and the whole was stirred at 5xc2x0 C.xcx9croom temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give N-benzyl-N-[2-(tert-butoxycarbonylamino)-3,3-diphenylpropyl]glycine ethyl ester (1.51 g) as a colorless oil.
MASS (APCI): 503 (M+H)+
Preparation 9
The following compound was obtained according to a similar manner to that of Preparation 8.
N-(2-tert-Butoxycarbonylamino-3,3-diphenylpropyl)-N-[2-methoxy-5-(trifluoromethoxy)benzyl]glycine methyl ester
NMR (CDCl3, xcex4): 1.32 (9H, s), 2.66 (1H, dd, J=14.5, 6.4 Hz), 2.87 (1H, dd, J=13.7, 4.2 Hz), 3.30 (1H, d, J=4.9 Hz), 3.61 (3H, s), 3.77 (3H, s), 3.82 (2H, m), 4.16 (1H, d, J=8.3 Hz), 4.61 (1H, m), 4.86 (1H, m), 6.81 (1H, d, J=8.9 Hz), 7.08-7.31 (13H, m)
MASS (APCI): 603 (M+H)+
Preparation 10
The following compounds were obtained according to a similar manner to that of Preparation 8 followed by a similar manner to that of Preparation 13.
(1) 6-Benzhydryl-3-methylpiperazin-2-one hydrochloride
NMR (DMSO-d6, xcex4): 1.39 (3H, m), 2.91 (1H, m), 3.14 (1H, m), 3.52-4.46 (3H, m), 4.70 (1H, m), 7.14-7.53 (10H, m)
MASS (APCI): 281 (M+H)+ (free)
(2) 6-Benzhydryl-3,3-dimethylpiperazin-2-one
NMR (CDCl3, xcex4): 1.35 (3H, s), 1.37 (3H, s), 2.74-2.95 (2H, m), 3.83 (1H, d, J=10.7 Hz), 4.24 (1H, m), 5.57 (1H, s), 7.17-7.35 (10H, m)
MASS (APCI): 295 (M+H)+
Preparation 1
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g) was added over 5 minutes to a mixture of N-(2-methoxybenzyl)glycine methyl ester hydrochloride (1.72 g), N-(tert-butoxycarbonyl)-3,3-diphenyl-L-alanine (1.71 g), 1-hydroxybenzotriazole (0.81 g) and N,N-diisopropylethylamine (1.22 ml) in dichloromethane (40 ml). After being stirred for 3 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1) to give N-[(2S)-2-(tert-butoxycarbonylamino)-3,3-diphenylpropionyl]-N-(2-methoxybenzyl)glycine methyl ester (2.34 g) as a colorless powder.
NMR (CDCl3, xcex4): 1.29 (9H, s), 3.62-3.77 (6H, m), 3.89 (1H, m), 4.13 (1H, m), 4.51 (2H, m), 4.86-5.07 (1H, m), 5.30-5.68 (1H, m), 6.44-7.38 (15H, m)
MASS (APCI): 555 (M+Na)+
Preparation 12
The following compound was obtained according to a similar manner to that of Preparation 11.
N-Benzyl-N-[(2R)-2-tert-butoxycarbonylamino-3,3-diphenylpropionyl]glycine ethyl ester
NMR (CDCl3, xcex4): 1.15-1.47 (12H, m), 3.61-4.25 (4H, m), 4.48-4.76 (2H, m), 4.99-5.17 (1H, m), 5.36-5.61 (1H, m), 6.61-7.43 (15H, m)
MASS (APCI): 417 (M+H)+
Preparation 13
4N Hydrogen chloride in ethyl acetate solution (10 ml) was added to a solution of N-[(2S)-2-(tert-butoxycarbonylamino)-3,3-diphenylpropionyl]-N-(2-methoxybenzyl)glycine methyl ester (1.34 g) in ethyl acetate (5 ml) at room temperature. After being stirred for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved into isopropyl alcohol (8 ml) and the solution was stirred for 3 hours under reflux. After being cooled with ice, the residue was triturated with diisopropyl ether (50 ml) and the resulting solid was collected by filtration to give (3S)-3-benzhydryl-1-(2-methoxybenzyl)piperazine-2,5-dione (785 mg) as a colorless powder.
NMR (DMSO-d6, xcex4): 3.01 (1H, d, J=17.4 Hz), 3.50 (1H, d, J=17.4 Hz), 3.75 (3H, s), 4.24 (1H, d, J=15.0 Hz), 4.38 (1H, d, J=15.0 Hz), 4.53 (1H, d, J=5.4 Hz), 4.73 (1H, d, J=5.4 Hz), 6.85-7.33 (14H, m), 8.39 (1H, m)
MASS (APCI): 423 (M+Na)+
Preparation 14
The following compound was obtained according to a similar manner to that of Preparation 13.
(3R) -3-Benzhydryl-1-benzylpiperazine-2,5-dione
NMR (DMSO-d6, xcex4): 2.98 (1H, d, J=17.2 Hz), 3.47 (1H, d, J=17.2 Hz), 4.16 (1H, d, J=14.5 Hz), 4.54 (1H, d, J=5.4 Hz), 4.57 (1H, d, J=14.5 Hz), 4.76 (1H, dd, J=5.4, 5.4 Hz), 7.07-7.41 (15H, m), 8.40 (1H, m)
MASS (APCI): 371 (M+H)+
Preparation 15
Sodium triacetoxyborohydride (5.6 g) was added portionwise to a mixture of glycine methyl ester hydrochloride (1.63 g), N,N-diisopropylethylamine (2.27 ml) and 2-methoxy-5-(trifluoromethoxy)benzaldehyde (3.8 g) in a mixture of dichloromethane (30 ml) and acetic acid (3 drops) at 0xc2x0 C. and the whole was stirred at 5xc2x0 C.xcx9croom temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give N-[2-methoxy-5-(trifluoromethoxy)benzyl]glycine methyl ester hydrochloride (2.76 g) as a colorless powder.
NMR (DMSO-d6, xcex4): 3.73 (3H, s), 3.86 (3H, s), 3.92 (2H, s), 4.10 (2H, s), 7.17 (1H, d, J=9.1 Hz), 7.42 (1H, dd, J=9.1, 2.6 Hz), 7.56 (1H, d, J=2.6 Hz), 9.68 (2H, br s)
MASS (APCI): 294 (M+H)+ (free)
Preparation 16
A mixture of (2S)-2-(4-methylphenylsulfonyloxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (26.2 g), 2-methoxybenzylamine (44 ml) and N,N-diisopropylethylamine (17.6 ml) in 1,3-dimethyl-2-imidazolidinone (393 ml) was stirred at 93xc2x0 C. for 7 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.7 g).
NMR (CDCl3, xcex4): 1.83-2.10 (6H, m), 2.57 (1H, m), 2.81 (1H, m), 3.27-3.66 (2H, m), 3.70-4.18 (5H, m), 5.10 (2H, s), 6.82-7.78 (9H, m)
MASS (APCI): 355 (M+H)+
Preparation 17
3-Bromo-1,1-diphenyl-2-propanone (12.7 g) and N,N-diisopropylethylamine (15.7 ml) were added successively to a solution of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.6 g) in tetrahydrofuran (156 ml) at 0xc2x0 C. After being stirred at room temperature for 2 hours, the mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 mlxc3x972). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a colorless syrup of (2S)-2-[[N-(2-oxo-3,3-diphenylpropyl)-N-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (1.51 g).
NMR (CDCl3, xcex4): 1.30-2.00 (3H, m), 2.23-2.70 (2H, m), 3.11-3.93 (8H, m), 3.74 (3H, s), 5.06 (2H, m), 5.36 (1H, m), 6.82-7.31 (19H, m)
MASS (APCI): 563 (M+H)+
Preparation 18
(2S)-2-[[N-(2-Oxo-3,3-diphenylpropyl)-(2-methoxybenzyl)amino]methyl]pyrrolidine-1-carboxylic acid benzyl ester (492 mg) was dissolved in a mixture of methanol (7.4 ml) and IN hydrochloric acid (0.5 ml), and the solution was hydrogenated over 10% palladiumxe2x80x94charcoal (50% wet) (0.15 g) at room temperature under atmospheric pressure for 15 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was partitioned between aqueous saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and the resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (221.2 mg) as a colorless solid.
NMR (CDCl3, xcex4): 1.29-1.37 (1H, m), 1.50-1.63 (2H, m), 1.74-1.84 (3H, m), 2.38 (1H, ddd, J=2.2, 9.5, 16.7 Hz), 2.43 (1H, dd, J=11.0, 11.0 Hz), 2.50 (1H, dd, J=11.6, 11.0 Hz), 2.66 (1H, dd, J=12.2 Hz), 2.73 (1H, dd, J=8.0, 8.5 Hz), 3.12 (1H, dd, J=11.6, 1.8 Hz), 3.33 (1H, ddd, J=8.7, 2.1, 11.0 Hz), 4.06 (1H, d, J=8.7 Hz), 7.12-7.43 (10H, m)
MASS (APCI): 293 (M+H)+
Preparation 19
Di-tert-butyl carbonate (3.24 g) was added to a mixture of (8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyridine dihydrochloride (3.62 g) and triethylamine (3.45 ml) in dichloromethane (100 ml) under ice-cooling. After being stirred at the same temperature for 3 hours, the reaction mixture was washed with water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (20:1). The earlier eluting fractions were collected and evaporated under reduced pressure to give brownish oil of (4S,8aS)-2-tert-butoxycarbonyl-4-benzhydryloctahydropyrrolo[1,2-a]pyridine (0.05 g).
NMR (CDCl3, xcex4): 1.38 (9H, s), 1.00-2.20 (5H, m), 2.80-3.00 (3H, m), 3.87 (1H, d, J=11.0 Hz), 4.15 (1H, dd, J=2.4, 12.8 Hz), 4.75 (1H, d, J=10.4 Hz), 4.70-4.90 (1H, m), 5.09 (1H, dd, J=2.9, 11.2 Hz), 7.05-7.40 (10H, m)
MASS (APCI): 393 (M+H)+, 337
The later eluting fractions were collected and evaporated under reduced pressure to give brownish oil of (4R,8aS)-2-tert-butoxycarbonyl-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine (1.5 g).
NMR (CDCl3, xcex4): 1.38 (9H, s), 1.00-1.95 (5H, m), 2.15-2.20 (1H, m), 3.37-2.55 (2H,. m), 2.70-2.75 (1H, m), 3.10-3.20 (1H, m), 3.70-3.85 (1H, m), 4.00-4.20 (1H, m), 4.05 (1H, d, J=8.4 Hz), 7.05-7.40 (10H, m)
MASS (APCI): 393 (M+H)+, 337
Preparation 20
The following compound was obtained according to a similar manner to that of Preparation 3.
(4R,8aS)-4-Benzhydryloctahydropyrrolo[1,2-a]pyridine dihydrochloride
NMR (DMSO-d6, xcex4): 1.50-5.00 (14H, m), 7.21-7.57 (10H, m), 9.50-10.20 (2H, m)
MASS (APCI): 393 (M+H)+ (free)
Preparation 21
The following compound was obtained according to a similar manner to that of Example 16.
Methyl [2-formyl-4-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenoxy]acetate
NMR (CDCl3, xcex4): 3.87 (3H, s), 4.91 (2H, s), 7.10 (1H, d, J=9.0 Hz), 7.66 (1H, dd, J=2.8, 9.0 Hz), 8.01 (1H, d, J=2.8 Hz), 10.58 (1H, s)
MASS (APIES negative): 329 (Mxe2x88x92H)+
Preparation 22
Propyl bromide (1 ml) was added to a mixture of 2-hydroxy-6-methoxybenzaldehyde (0.45 g), potassium carbonate (0.83 g) and a small amount of potassium iodide in a mixed solvent of N,N-dimethylformamide (10 ml) and acetone (5 ml). After being stirred for 5 hours at 100xc2x0 C., the mixture was poured into ice-water (20 ml) and extracted with ethyl acetate. The extract was washed with brine (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 2-methoxy-6-propoxybenzaldehyde (0.3 g).
NMR (CDCl3, xcex4): 1.05 (3H, t, J=7.4 Hz), 1.83 (2H, sext, J=7.4 Hz), 3.89 (3H, s), 4.00 (2H, t, J=6.5 Hz), 6.55 (2H, d, J=8.5 Hz), 7.38 (1H, t, J=8.5 Hz), 10.75 (1H, s)
MASS (APCI): 195 (M+H)+
Preparation 23
The following compounds were obtained according to a similar manner to that of Preparation 22.
(1) 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzaldehyde
NMR (CDCl3, xcex4): 3.91 (3H, s), 4.41 (2H, q, J=8.0 Hz), 6.56 (1H, d, J=8.2 Hz), 6.72 (1H, d, J=8.3 Hz), 7.47 (1H, t, J=8.4 Hz), 10.51 (1H, s)
MASS (APCI): 235(M+H)+
(2) 2-Ethoxy-6-methoxybenzaldehyde
NMR (CDCl3, xcex4): 1.43 (3H, t, J=7.6 Hz), 4 12 (2H, q, J=7.6 Hz), 3.89 (3H, s), 6.53 (2H, d, J=8.5 Hz), 7.38 (1H, t, J=8.5 Hz), 10.53 (1H, s)
MASS (APCI): 181 (M+H)+
Preparation 24
Thionyl chloride (0.58 ml) was added dropwise to a solution of L-pipecolinic acid (450 mg) in methanol at room temperature. The reaction mixture was stirred at 55xc2x0 C. for 2 hours. The whole mixture was evaporated under reduced pressure to give (2S)-piperidine-2-carboxylic acid methyl ester hydrochloride as a colorless oil.
NMR (DMSO-d6, xcex4): 1.55-1.75 (4H, m), 2.04-2.10 (1H, m), 2.49-2.51 (1H, m), 2.91 (1H, m), 3.20-3.27 (1H, m), 3.77 (3H, s), 4.08 (1H, m), 9.20-9.50 (2H, m)
MASS (APCI): 144 (M+H)+ (free)
Preparation 25
(2S)-Piperidine-2-carboxylic acid methyl ester hydrochloride (625 mg) was dissolved in dichloromethane. Then N,N-diisopropylethylamine (0.91 ml) and benzaldehyde (0.53 ml) were added to the solution at 0xc2x0 C. After the whole was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (1.48 g) was added. The reaction mixture was allowed to room temperature and stirred for 3 hours. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give (2S)-1-benzylpiperidine-2-carboxylic acid methyl ester (795 mg).
NMR (DMSO-d6, xcex4): 1.26-1.86 (6H, m), 2.04-2.20 (1H, m), 2.88-2.99 (1H, m), 3.16 (1H, dd, J=4.9, 7.3 Hz), 3.40 (1H, d, J=13.3 Hz), 3.74 (3H, s), 3.78 (1H, d, J=13.3 Hz), 7.22-7.38 (5H, m)
MASS (APCI): 234 (M+H)+
Preparation 26
Lithium aluminum hydride was added to an ice-cooled solution of (2S)-1-benzylpiperidine-2-carboxylic acid methyl ester (178 mg) in tetrahydrofuran (2.7 ml) under nitrogen atmosphere. The mixture was stirred for 2 hours below 5xc2x0 C. The reaction was quenched by a sequential addition of water (0.12 ml), 15% aqueous sodium hydroxide (0.12 ml) and water (0.36 ml) successively, and the whole was stirred at room temperature for 1 hour. The insoluble materials were removed by filtration. The filtrate was dried over sodium sulfate and evaporated under reduced pressure to give (2S)-1-benzyl-2-(hydroxymethyl)piperidine as a colorless oil.
NMR (CDCl3, xcex4): 1.25-1.72 (6H, m), 1.97-2.19 (2H, m), 2.43-2.49 (1H, m), 2.82-2.90 (1H, m), 3.32 (1H, d, J=13.4 Hz), 3.51 (1H, dd, J=3.9, 10.8 Hz), 3.87 (1H, dd, J=4.2, 10.8 Hz), 4.06 (1H, d, J=13.4 Hz), 7.20-7.38 (5H, m)
MASS (APCI): 206 (M+H)+
Preparation 27
A solution of dimethyl sulfoxide (0.219 ml) in dichloromethane (1.1 ml) was added dropwise to a solution of oxalyl chloride (0.133 ml) in dichloromethane (2.7 ml) under cooling below xe2x88x9260xc2x0 C. with dry ice-acetone. After 5 minutes, the mixture was allowed to xe2x88x9210xc2x0 C., and a solution of (2S)-1-benzyl-2-(hydroxymethyl)piperidine (156.5 mg) in dichloromethane (1.6 ml) was added to the mixture. The whole mixture was then cooled below xe2x88x9260xc2x0 C. and was stirred for 20 minutes at the same temperature. After addition of triethylamine (0.64 ml) followed by stirring at room temperature, the reaction mixture was poured into water and extracted with 1,2-dichloroethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. Benzylamine (0.33 ml) was added to the solution of the syrup obtained above procedure in 1,2-dichloroethane (2.5 ml) with ice-cooling. After the whole was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (0.323 g) was added to this mixture. The reaction mixture was allowed to room temperature and was stirred for 3 hours. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography using a mixture of dichloromethane and methanol (20:1) as an eluent to give N-benzyl-[(2S)-1-benzylpiperidin-2-ylmethyl]amine (168.5 mg).
NMR (CDCl3, xcex4): 1.26-1.49 (3H, m), 1.56-1.67 (3H, m), 2.03 (1H, s), 2.04-2.14 (1H, m), 2.42-2.50 (1H, m), 2.66-2.86 (3H, m), 3.25 (1H, d, J=13.6 Hz), 3.73 (2H, s), 3.92 (1H, d, J=13.6 Hz), 7.19-7.38 (20H, m)
MASS (APCI): 295 (M+H)+
Preparation 28
The following compound was obtained according to a similar manner to that of Preparation 17.
3-[N-[((2S)-1-Benzylpiperidin-2-yl)methyl]-N-benzylamino]-1,1-diphenylpropan-2-one
NMR (CDCl3, xcex4): 1.22-1.85 (5H, m), 2.34 (1H, m), 2.61 (2H, m), 2.88-2.95 (1H, m), 3.22 (1H, m), 3.41 (2H, s), 3.66 (2H, s), 4.03 (1H, d, J=15.0 Hz), 4.43 (1H, d, J=5.70 Hz), 5.27 (1H, s), 7.16-7.34 (20H, m)
MASS (APCI): 503 (M+H)+
Preparation 29
The following compound was obtained according to a similar manner to that of Preparation 25.
(2R)-2-(Benzyloxycarbonylamino)-3-(2-methoxybenzylamino)propionic acid methyl ester
NMR (CDCl3, xcex4): 2.90 (1H, dd, J=4.7, 12.5 Hz), 3.01 (1H, dd, J=4.8, 12.5 Hz), 3.73-3.89 (9H, m), 4.40 (1H, m), 5.82 (1H, br), 6.83-7.55 (9H, m)
MASS (APCI): 373 (M+H)+
Preparation 30
The following compounds were obtained according to a similar manner to that of Preparation 17.
(1) (2R)-2-(Benzyloxycarbonylamino)-3-[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]propionic acid methyl ester
NMR (CDCl3, xcex4): 3.08 (2H, d, J=5.6 Hz), 3.42 (2H, s), 3.60 (2H, s), 3.70 (3H, s), 3.75 (3H, s), 3.77 (1H, m), 4.26 (1H, m), 5.00 (1H, s), 5.12 (1H, s), 6.41 (1H, d, J=7.0 Hz), 6.72-7.34 (19H, m)
MASS (ESI): 581(M+H)+, 603 (M+Na)+
(2) 3-[N-Benzyl-N-[(4-benzylmorpholin-3-yl)methyl]amino]-1,1-diphenylpropan-2-one
IR (Neat): 1724 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.05-2.17 (1H, m), 2.40-2.70 (3H, m), 2.98 (1H, dd, J=3.6, 13.2 Hz), 3.13 (1H, d, J=13.4 Hz), 3.51 (2H, s), 3.67 (2H, s), 3.41-3.65 (1H, m), 3.86 (1H, dd, J=3.0, 11.2 Hz), 4.04 (1H, d, J=13.4 Hz), 5.10 (1H, s), 7.14-7.34 (20H, m)
MASS (APCI): 504 (M+H)+
Preparation 31
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimido hydrochloride (5.74 g) was added to a solution of (3S)-4-benzyl-5-oxomorpholine-3-carboxylic acid (10.0 g), benzylamine (4.65 ml), 1-hydroxybenzotriazole (5.74 g) and triethylamine (8.89 ml) in dichloromethane (100 ml) under ice-cooling. After being stirred for 15 hours at room temperature, the reaction mixture was washed with aqueous sodium carbonate, 1N hydrochloric acid and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of toluene and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of N-benzyl((3S)-4-benzyl-5-oxomorpholin-3-yl)amide (11.6 g).
NMR (CDCl3, xcex4): 3.72 (1H, dd, J=3.9, 12.0 Hz), 3.79 (1H, d, J=14.6 Hz), 3.70-3.85 (1H, m), 4.18 (2H, q, J=17.0 Hz), 4.27-4.35 (1H, m), 4.37 (1H, dd, J=5.6, 14.8 Hz), 4.56 (1H, dd, J=5.6, 14.8 Hz), 5.46 (1H, d, J=14.6 Hz), 6.80-6.90 (1H, m), 7.20-7.50 (10H, m)
MASS (APCI): 325 (M+H)+
Preparation 32
Lithium aluminum hydride (4.7 g) was added by small portions to a solution of N-benzyl((3S)-4-benzyl-5-oxomorpholin-3-yl)amide (8.0 g) in tetrahydrofuran (50 ml) under nitrogen atmosphere, and the whole was stirred at 70xc2x0 C. for 15 hours. After being cooled with ice, 2N sodium hydroxide (2 ml) was added to the mixture under nitrogen atmosphere. The resulting precipitates were filtered off and washed with tetrahydrofuran, and the filtrate and the washings were combined and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (9:1). The fractions containing the objective compound were collected, evaporated under reduced pressure to give an oil of N-benzyl[(4-benzylmorpholin-3-yl)methyl]amine (2.4 g).
NMR (CDCl3, xcex4): 2.18-2.29 (1H, m), 2.50-2.92 (4H, m), 3.17 (1H, d, J=13.4 Hz), 3.51-3.86 (7H, m), 3.99 (1H, d, J=13.4 Hz), 7.21-7.31 (10H, m)
MASS (APCI): 297 (M+H)+
Preparation 33
The following compound was obtained according to a similar manner to that of Preparation 18.
(6R,9aR)-6-Benzhydryl-8-tert-butoxycarbonyloctahydropyrazino[2,1-c][1,4]oxazine
IR (Nujol): 3400, 1715, 1605, 1530, 1500, 1450, 1240, 1200, 1120 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.33 (9H, s), 2.00-3.72 (12H, m), 4.18 (1H, d, J=7.4 Hz), 7.16-7.31 (10H, m)
MASS (APCI): 409 (M+H)+
Preparation 34
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.11 g) was added over 5 minutes to a mixture of N,0-dimethylhydroxylamine hydrochloride (1.17 g), (2S)-piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.64 g), 1-hydroxybenzotriazole (1.49 g) and N,N-diisopropylethylamine (2.1 ml) in dichloromethane (40 ml). After being stirred for 18 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1) to give 2-(N-methoxy-N-methylcarbamoyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.61 g) as a colorless powder.
NMR (CDCl3, xcex4): 1.45 (9H, s), 2.90-3.20 (5H, m), 3.60-4.20 (6H, m), 4.41 (1H, m), 4.90 (1H, m), 5.06 (1H, d, J=12.4 Hz), 5.16 (1H, d, J=12.4 Hz), 7.33 (5H, m)
MASS (APCI): 308 (Mxe2x88x92Boc+H)+
Preparation 35
Lithium aluminum hydride (38 mg) was added by small portions to an ice-cooled solution of 2-(N-methoxy-N-methylcarbamoyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (407 mg) in tetrahydrofuran (5 ml) below 5xc2x0 C. under nitrogen atmosphere. After the mixture was stirred at the same temperature for 2.5 hours, 2N sodium hydroxide (0.2 ml) was added to the mixture. After the mixture was stirred for 30 minutes, the insoluble materials were removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were combined, and evaporated under reduced pressure to give a residue. Sodium triacetoxyborohydride (424 mg) was added portionwisely to a stirred mixture of the residue obtained in the above procedure and 2-methoxybenzylamine (151 mg) in dichloromethane (4 ml). After being stirred at room temperature for 4 hours, 3-bromo-1,1-diphenyl-2-propanone (347 mg) in N,N-dimethylformamide (5 ml) and N,N-diisopropylethylamine (0.35 ml) were added successively to the reaction mixture at 5xc2x0 C. The whole mixture was stirred at room temperature for 36 hours and then poured into ice-water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1) to give (2R)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (170 mg) as a colorless powder.
NMR (CDCl3, xcex4): 1.41-1.57 (9H, m), 2.70-3.00 (5H m), 3.25-4.35 (11H, m), 4.95-5.15 (3H, m), 6.70-7.29 (19H, m)
Preparation 36
To a solution of (1RS,2RS)-1,2-cyclohexanediamine (114 mg) in N,N-dimethylformamide (4 ml) were added 3-bromo-1,1-diphenyl-2-propanone (289 mg) and sodium triacetoxyborohydride (268 mg) successively and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate three times. After the combined extract was washed with water, the organic phase was extracted with 1N hydrochloric acid. The aqueous phase was adjusted to pH 9-10 with sodium hydroxide under ice-cooling and then extracted with ethyl acetate three times. The combined extract was washed with water and brine successively, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml) and to the solution were added triethylamine (404 mg) and di-tert-butyl dicarbonate (436 mg) successively. After the mixture was stirred at ambient temperature for 3 hours, the volatile materials were removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with a mixture of ethyl acetate and hexane (1:3) to give 161 mg of tert-butyl (3RS,4aSR,8aSR)-3-benzhydryloctahydroquinoxaline-1-carboxylate as a mixture with some impurities. Purification of this product by preparative thin layer chromatography (40% ethyl acetate in hexane) gave tert-butyl (3RS,4aSR,8aSR)-3-benzhydryloctahydroquinoxaline-1-carboxylate (42.3 mg).
NMR (CDCl3, xcex4): 1.12-1.90 (8H, m), 1.36 (9H, s), 2.34 (1H, br d, J=12.8 Hz), 2.57-2.67 (1H, m), 2.80-2.95 (2H, m), 3.57-3.83 (3H, m), 7.16-7.38 (10H, m)
MASS (APCI): 407 (M+H)+
Preparation 37
Tert-Butyl (3RS,4aSR,8aSR)-3-benzhydryloctahydroquinoxaline-1-carboxylate (42 mg) was dissolved in 4N ethyl acetate solution of hydrogen chloride (4 ml) and the mixture was stirred at ambient temperature for 3 hours. The volatile materials were removed under reduced pressure to give (2RS,4aSR,8aSR)-2-benzhydryldecahydroquinoxaline dihydrochloride (28 mg).
NMR (CDCl3, xcex4) 1.20-2.15 (8H, m), 3.39-3.66 (8H, m), 4.88 (1H, d, J=11.2 Hz), 7.26-7.59 (10H, m)
MASS (APCI): 307 (M+H)+ (free)
Preparation 38
The following compound was obtained according to a similar manner to that of Preparation 36.
Tert-Butyl (3RS,4aSR,8aRS)-3-benzhydryloctahydroquinoxaline-1-carboxylate
NMR (CDCl3, xcex4): 1.11-2.12 (9H, m), 1.34 (9H, s), 3.13-3.28 (2H, m), 3.36-3.81 (2H, m), 4.02-4.14 (1H, m), 4.49 (1H, d, J=11.5 Hz), 7.06-7.40 (10H, m)
MASS (APCI): 407 (M+H)+
Preparation 39
Tert-Butyl (3RS,4aSR,8aRS)-3-benzhydryloctahydroquinoxaline-1-carboxylate (100 mg) was dissolved in hydrogen chloride (5 ml, 4N solution in ethyl acetate) and the mixture was stirred at ambient temperature for 3 hours. The volatile materials were removed under reduced pressure to give (2RS,4aRS,8aSR)-2-benzhydryldecahydroquinoxaline dihydrochloride, which was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted to pH 9-10 and extracted with ethyl acetate three times. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give (2RS,4aRS,8aSR)-2-benzhydryldecahydroquinoxaline (88 mg).
NMR (CDCl3, xcex4): 1.19-1.83 (9H, m), 2.19-2.36 (1H, m), 2.51 (1H, dd, J=11.4 and 9.4 Hz), 2.73-2.87 (2H, m), 3.07 (1H,. d, J=2.9 Hz), 3.63-3.82 (2H, m), 7.10-7.42 (10H, m)
MASS (APCI): 307 (M+H)+
Preparation 40
The following compound was obtained according to a similar manner to that of Example 14 from 3-formyl-4-methoxyphenylboronic acid.
2-Methoxy-5-(4-pyridyl)benzaldehyde
NMR (CDCl3, xcex4): 4.00 (3H, s), 7.12 (1H, m), 7.45-7.53 (2H, m), 7.85 (1H, dd, J=2.5, 8.7 Hz), 8.14 (1H, m), 8.64-8.97 (2H, m), 10.52 (1H, s)
MASS (APCI): 214 (M+H)+
Preparation 41
The following compounds were obtained according to a similar manner to that of Preparation 22 from each corresponding hydroxybenzaldehyde.
(1) 2-Ethoxy-4,6-dimethoxybenzaldehyde
NMR (CDCl3, xcex4): 1.46 (3H, t, J=7.0 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.09 (2H, q, J=7.0 Hz), 6.07 (2H, s), 10.38 (1H, s)
MASS (APCI): 211 (M+H)+
(2) 2-Isopropoxy-4,6-dimethoxybenzaldehyde
NMR (CDCl3, xcex4): 1.38 (6H, d, J=6.1 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.59 (1H, m), 6.06 (1H, d, J=2.1 Hz), 6.08 (1H, d, J=2.1 Hz), 10.36 (1H, s)
MASS (ESI): 247 (M+Na)+
(3) 5-(1H-Imidazol-1-yl)-2-methoxybenzaldehyde
NMR (CDCl3, xcex4): 4.00 (3H, s), 7.06-7.85 (6H, m), 10.50 (1H, s)
MASS (APCI): 203 (M+H)+
Preparation 42
The following compound was obtained according to a similar manner to that of Preparation 27.
Benzyl (2S)-2-[(benzylamino)methyl]-1-pyrrolidinecarboxylate
IR (neat, FTxe2x80x94IR): 3410, 2765, 1695, 1420, 1355 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.69-2.12 (4H, m), 3.20 (2H, br s), 4.04-4.26 (3H, m), 5.01-5.16 (2H, m), 7.26-7.53 (10H, m)
MASS (APCI): 325 (M+H)+
Preparation 43
The following compound was obtained according to a similar manner to that of Preparation 17.
Benzyl (2S)-2-[[benzyl[3,3-bis(4-fluorophenyl)-2-oxopropyl]amino]methyl]-1-pyrrolidinecarboxylate
IR (neat, FT-IR): 1700, 1415, 1335 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.48-5.30 (16H, m), 6.91-7.33 (18H, m)
MASS (APCI): 569 (M+H)+
Preparation 44
The following compound was obtained according to a similar manner to that of Preparation 18.
(4R,8aS)-4-[Bis(4-fluorophenyl)methyl]-octahydropyrrolo[1,2-a]pyrazine
Preparation 45
The following compound was obtained according to a similar manner to that of Preparation 34.
Benzyl (2S)-2-(N-methoxy-N-methylcarbamoyl)-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 1.82-2.26 (4H, m), 3.10-3.22 (3H, m), 3.49-3.72 (2H, m), 3.41-3.80 (3H, m), 4.63-4.81 (1H, m), 5.00-5.23 (2H, m), 7.27-7.38 (5H, m)
MASS (APCI): 293 (M+H)+
Preparation 46
Methyl magnesium bromide in tetrahydrofuran (1M, 36.9 ml) was added into a solution of benzyl (2S)-2-(N-methoxy-N-methylcarbamoyl)-1-pyrrolidinecarboxylate (3.6 g) in tetrahydrofuran (36 ml) under ice-cooling. After being stirred for 2 hours at the same temperature, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give benzyl (2S)-2-acetyl-1-pyrrolidinecarboxylate (0.81 g).
NMR (CDCl3, xcex4): 1.71-2.27 (7H, m), 3.51-3.63 (2H, m), 4.28-4.45 (1H, ddd, J=4.6, 8.4, 13 Hz), 5.02-5.21 (2H, m), 7.26-7.36 (5H, m)
MASS (APCI): 248 (M+H)+
Preparation 47
The following compound was obtained according to a similar manner for Preparation 25 from benzyl (2S)-2-acetyl-1-pyrrolidinecarboxylate.
Benzyl (2S)-2-[1-(benzylamino)ethyl]-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 1.01-2.04 (8H, m), 2.99-4.45 (6H, m), 5.10 (2H, br), 7.21-7.32 (10H, m)
MASS (APCI): 339 (M+H)+
Preparation 48
The following compound was obtained according to a similar manner to that of Preparation 17 from benzyl (2S)-2-[1-(benzylamino)ethyl]-1-pyrrolidinecarboxylate.
Benzyl (2S)-2-[1-[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]ethyl]-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 0.81-5.24 (23H, m), 7.13-7.79 (15H, m)
MASS (APCI): 547 (M+H)+
Preparation 49
Benzyl (2S)-2-[1-[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]ethyl]-1-pyrrolidinecarboxylate was dissolved in a mixture of methanol (4 ml), tetrahydrofuran (0.5 ml) and 1N-hydrochloric acid (0.41 ml). The solution was hydrogenated over 10% palladium-charcoal (50% wet) at room temperature under 3 atom pressure for 5 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was partitioned between aqueous saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of dichloromethane and methanol (6:1) as an eluent. The earlier and later fractions were separately collected and evaporated under reduced pressure separately to give each colorless oil, which were used for next steps separately.
The later eluting fractions of (1R or 1S,4R,8aS)-4-benzhydryl-1-methyloctahydropyrrolo[1,2-a]pyrazine
NMR (CDCl3, xcex4): 1.04-4.10 (16H, m), 6.90-7.42 (10H, m)
MASS (APCI): 307 (M+H)+
The earlier eluting fractions of (1S or 1R,4R,8aS)-4-benzhydryl-1-methyloctahydropyrrolo[1,2-a]pyrazine
NMR (CDCl3, xcex4): 1.04-2.82 (12H, m), 3.44-4.17 (4H, m), 6.90-7.42 (10H, m)
MASS (APCI): 307 (M+H)+
Preparation 50
The following compound was obtained according to a similar manner to that of Preparation 27.
Benzyl (2S,4R)-2-[(benzylamino)methyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate
IR (Neat): 1702, 1422, 1504 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.89 (9H, s), 0.13 (6H, s), 1.90-2.00 (2H, m), 2.70-2.85 (2H, m), 3.40-3.50 (2H, m), 3.70-3.85 (2H, m), 4.11 (1H, br s), 4.35-4.45 (1H, m), 5.05-5.20 (2H, m), 7.16-7.35 (10H, m)
MASS (APCI): 455 (M+H)+ (free)
Preparation 51
The following compound was obtained according to a similar manner to that of Preparation 17.
Benzyl (2S,4R)-2-[[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4) 0.13 (6H, s), 0.82 (9H, s), 1.60-4.20 (12H, m), 5.00-5.20 (3H, m), 7.16-7.35 (20H, m)
MASS (APCI): 685 (M+Na), 663 (M+H)+, 505, 455, 415, 356
Preparation 52
A solution of (2S,4R)-2-[[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]-4-[(tert-butyldimethylsilyl)oxy]-1-pyrrolidinecarboxylate (4.82 g) and acetic acid (0.87 g) in methanol (100 ml) was hydrogenated over 10% palladium-charcoal (50% wet, 1.0 g) at room temperature under 2-3 atoms for 15 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (4.05 g) as a syrup.
IR (KBr): 3400, 1648, 1504 cmxe2x88x921 
NMR (CDCl3, xcex4): xe2x88x920.20-xe2x88x920.11 (6H, m), 0.74-0.81 (9H, m), 2.03 (6H, s), 1.60-1.80 (2H, m), 2.00-4.70 (10H, m), 7.16-7.35 (10H, m)
MASS (APCI): 423 (M+H)+ (free)
Preparation 53
Di-tert-butyl dicarbonate (4.4 g) was added to an ice-cooled mixture of bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (7.6 g) and triethylamine (4.9 ml) in dichloromethane (200 ml). After being stirred at the same temperature for 3 hours the reaction mixture was washed with water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The eluting fractions were collected and evaporated under reduced pressure to give colorless oil of tert-butyl (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (6.9 g). This compound (6.88 g) was dissolved into 1M tetrabutylammonium floride in tetrahydrofuran (65 ml). After being stirred for 3 hours at room temperature the reaction mixture was poured into water, the whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The later eluting fractions were collected and evaporated under reduced pressure to give colorless oil of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.3 g).
IR (neat): 1695, 1504 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.43 (9H, s), 1.31-1.74 (3H, m), 2.20-2.75 (3H, m), 1.93 (1H, dd, J=4.2 and 9.9 Hz), 3.08 (1H, dd, J=6.1 and 9.9 Hz), 3.30-3.40 (1H, m), 3.60-3.70 (1H, m), 3.78 (1H, br s), 3.94 (1H, d, J=9.0 Hz), 4.15-4.19 (1H, m), 7.13-7.45 (10H, m)
MASS (APCI): 409 (M+H)+ (free)
The earlier eluting fractions were collected and evaporated under reduced pressure to give colorless oil of tert-butyl (4S,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.5 g).
NMR (CDCl3, xcex4) 1.32 (9H, s), 1.50-2.00 (3H, m), 2.40-2.55 (2H, m), 3.00-3.10 (2H, m), 3.40-4.05 (5H, m), 4.30 (1H, d, J=11.2 Hz), 7.15-7.45 (10H, m)
MASS (APCI): 409 (M+H)+ (free)
Preparation 54
Methyl iodide (23 xcexcl) was added to an ice-cooled mixture of tert-butyl (4S,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (155 mg) and cetyltrimethylammonium bromide (15 mg) and finely powdered sodium hydroxide (76 mg) in dichloromethane (2 ml), and the whole was stirred for 5 hours. Additional methyl iodide (23 xcexcl) was added to the mixture and the mixture was further stirred overnight. The resulting mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected to give tert-butyl (4S,7R,8aS)-4-benzhydryl-7-methoxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (56 mg) as a syrup.
IR (neat): 3400, 1691, 1504 cmxe2x88x921 
MASS (APCI): 423 (M+H)+
Preparation 55
The following compound was obtained according to a similar manners to that of Preparations 54 and 37.
(4R,7R,8aS)-4-Benzhydryl-7-methoxyoctahydropyrrolo[1,2-a]pyrazine dihydrochloride
MASS (APCI): 323 (M+H)+
Preparation 56
Methanesulfonyl chloride (0.18 ml) was added dropwise to an ice-cooled solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.78 g) and triethylamine (0.53 ml) in dichlorometane. After being stirred for 3 hours at the same temperature the mixture was washed with aqueous saturated sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The syrup obtained by above procedure and sodium azide (126 mg) was dissolved into dimethylsulfoxide (5 ml). The whole was stirred at 75xc2x0 C. for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (30:1). The fractions containing the objective compound were collected to give (4R,7S,8aS)-4-benzhydryl-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-7-azide (0.70 mg).
NMR (CDCl3, xcex4): 1.30-1.40 (2H, m), 1.38 (9H, s), 1.98-2.06 (1H, m), 2.15-2.27 (2H, m), 2.31-2.65 (2H, m), 2.78 (1H, d, J=8.6 Hz), 3.00-3.20 (1H, m), 3.63-3.72 (2H, m), 4.04 (1H, d, J=8.7 Hz), 7.13-7.43 (10H, m)
MASS (APCI): 434 (M+H)+ (free)
Preparation 57
10% Palladium-charcoal (50% wet, 40 mg) and 0.1N hydrochloric acid (0.1 ml) were added into a solution of tert-butyl (4R,7R,8aS)-7-azido-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (200 mg) in methanol (2.5 ml) at room temperature. The mixture was hydrogenated at room temperature under atmospheric pressure for 4 hours. The palladium was filtered and washed with methanol. The filtrate and washings were combined and concentrated in vacuo. The resulting residue was partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of dichloromethane and methanol (15:1) as an eluent. The fractions containing the objective compound were collected to give tert-butyl (4R,7R,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (193 mg).
NMR (CDCl3, xcex4): 1.22-1.65 (15H, m), 2.30-2.51 (3H, m), 3.00-3.40 (2H, m), 3.68-4.10 (3H, m), 7.13-7.42 (10H, m)
MASS (APCI): 408 (M+H)+
Preparation 58
The following compound was obtained according to a similar manner to that of Preparation 57.
Tert-Butyl (4R,7S,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate
IR (KBr): 3300-3100, 1697 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.00-1.10 (1H, m), 1.38(9H, s), 1.80-3.80 (10H, m), 4.07 (1H, d, J=8.0 Hz), 7.13-7.40 (10H, m)
MASS (APCI): 408 (M+H)+
Preparation 59
Sodium triacetoxyborohydride (241 mg) was added to an ice-cooled solution of tert-butyl (4R,7S,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.23 g) and aqueous 30% formaldehyde (0.17 ml) in dichloromethane (10 ml). After being stirred for 15 hours at room temperature the mixture was washed with aqueous saturated sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-(dimethylamino)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (210 mg).
NMR (CDCl3, xcex4): 1.20-1.40 (1H, m), 1.37 (9H, s), 1.90-4.20 (10H, m), 2.06 (6H, s), 4.06 (1H, d, J=8.0 Hz), 7.13-7.41 (10H, m)
MASS (APCI): 436 (M+H)+
Preparation 60
The following compound was obtained according to a similar manner to that of Preparation 3.
N-[(4R,7S,8aS)-4-Benzhydryloctahydropyrrolo[1,2-a]pyrazin]-7-N,N-dimethylamine trihydrochloride
IR (KBr): 3400, 1648, 1504 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.50-4.10 (15H, m), 4.26 (1H, d, J=9.0 Hz), 7.20-7.43 (10H, m), 9.20-9.60 (3H, m), 10.91 (1H, br s)
MASS (APCI): 336 (M+H)+ (free)
Preparation 61
A solution of benzyl chloroformate (58 xcexcl) in dichloromethane (0.5 ml) was added dropwise to an ice-cooled solution of tert-butyl (4R,7S,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate and triethylamine (96 xcexcl) in dichloromethane (2 ml), and the whole was stirred for 2 hours at the same temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-[(benzyloxycarbonyl)amino]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (190 mg) as a syrup.
NMR (CDCl3, xcex4): 1.00-1.20 (1H, m), 1.37 (9H, s), 2.00-2.70 (6H, m), 3.00-3.10 (1H, m), 3.70-4.20 (3H, m), 4.02 (1H, d, J=8.0 Hz), 4.98 (1H, d, J=8.6 Hz), 5.06 (2H, s), 7.13-7.40 (15H, m)
MASS (APCI): 542 (M+H)+
Preparation 62
The following compound was obtained according to a similar manner to that of preparation 3.
Benzyl (4R,7S,8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazin-7-ylcarbamate dihydrochloride
NMR (CDCl3, xcex4): 1.40-5.10 (15H, m), 4.60 (2H, s), 7.16-7.80 (13H, m), 8.21 (1H, br s)
MASS (APCI): 442 (M+H)+ (free)
Preparation 63
(Dimethylamino)sulfur trifluoride (0.068 ml) was added dropwise to a solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (115 mg) in dichloromethane (2 ml) under cooling with dry ice-acetone. The mixture was stirred for 20 minutes at the same temperature (xe2x88x9250xc2x0 C.), followed by room temperature for 2 hours. The mixture was poured into ice-water and the dichloromethane layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting syrup was treated with 4N hydrogen chloride in ethyl acetate (2 ml) and evaporated under reduced pressure to give (4R,7S,8aS)-4-benzhydryl-7-fluorooctahydropyrrolo[1,2-a]pyrazine dihydrochloride (75 mg).
MASS (APCI): 311 (M+H)+, 333 (M+Na) (free)
Preparation 64
Triphenylphosphine (860 mg), acetic acid (159 mg) and diisopropyl azodicarboxylate were added successively into a solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (670 mg) in tetrahydrofuran (10 ml) at room temperature. After being stirred for 1 hour at room temperature, the reaction mixture was poured into aqueous saturated sodium hydrogen carbonate. The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (2:1-3:2) as an eluent to give tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.
NMR (CDCl3, xcex4): 1.30-1.43 (11H, m), 2.01-2.04 (3H, m), 2.08-2.79 (6H, m), 3.12 (1H, m), 3.77-4.10 (2H, m), 4.89-5.01 (1H, m), 6.71-7.42 (10H, m)
MASS (APCI): 451 (M+H)+
Preparation 65
Sodium methoxide in methanol (5M, 27 xcexcl ) was added into a solution of tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (628 mg) in methanol (10 ml) at room temperature. After being stirred for 1 hour at the same temperature, the reaction mixture was poured into water (10 ml). The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (521 mg).
NMR (CDCl3, xcex4): 1.20-1.38 (11H, m), 1.80-1.98 (2H, m), 2.14-2.33 (2H, m), 2.43-2.74 (3H, m), 3.10 (1H, br), 3.73 (1H, br), 4.04-4.09 (2H, m), 7.14-7.41 (10H, m)
MASS (APCI): 409 (M+H)+
Preparation 66
Sodium hydride (60% in mineral oil, 14.9 mg) was added into a solution of tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (126.8 mg) in N,N-dimethylformamide (1.5 ml) under ice-cooling. After being stirred for 0.5 hour at the same temperature, methyl iodide was added to the reaction mixture. And this mixture was stirred for 12 hours at room temperature. Then the reaction mixture was poured into water (10 ml). The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:2) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-methoxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (100.5 mg).
NMR (CDCl3, xcex4): 1.38 (11H, br), 1.80-1.88 (1H, m), 2.04-2.80 (5H, m), 3.14 (3H, s), 3.63-4.18 (4H, m), 7.14-7.45 (10H, m)
MASS (APCI): 423 (M+H)+
Preparation 67
The following compound was obtained according to a similar manner to that of Preparation 63 from tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.
Tert-Butyl (4R,7R,8aS)-4-benzhydryl-7-fluorohexahydropyrrolo[1,2-a]pyrazine-2 (1H)-carboxylate
NMR (CDCl3, xcex4): 1.22-2.58 (15H, m), 3.12-4.18 (2H, m), 3.79-4.18 (3H, m), 4.84-5.14 (1H, m), 7.15-7.42 (10H, m)
MASS (APCI): 411 (M+H)+
Preparation 68
The following compound was obtained according to a similar manner to that of Preparation 3.
(4S,7R,8aS)-4-Benzhydryl-7-methoxyoctahydropyrrolo[1,2-a]pyrazine dihydrochloride
MASS (APCI): 323 (M+H)+ (free)
Preparation 69
The following compound was obtained according to a similar manner to that of Preparation 46 from tert-butyl (2S,3S)-3-hydroxy-2-(N-methoxy-N-methylcarbamoyl)-1-pyrrolidinecarboxylate.
Tert-Butyl (2S,3S)-2-formyl-3-hydroxy-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 1.47 (9H, s), 1.89-2.04 (1H, m), 3.43-4.48 (6H, m), 9.68 (1H, d)
MASS (ESI): 238 (M+Na)
Preparation 70
The following compound was obtained according to a similar manner to that of Preparation 25 from tert-butyl (2S,3S)-2-formyl-3-hydroxy-1-pyrrolidinecarboxylate.
Tert-Butyl (2R,3S)-3-hydroxy-2-[[(2-methoxybenzyl)amino]ethyl]-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 1.47 (9H, m), 1.70-2.20 (5H, m), 2.99-4.52 (5H, m), 3.85 (3H, m), 6.85-6.95 (2H, m), 7.20-7.31 (4H, m)
MASS (APCI): 337 (M+1)
Preparation 71
The following compound was obtained according to a similar manner to that of Preparation 17 from tert-butyl (2R,3S)-3-hydroxy-2-[[(2-methoxybenzyl)amino]methyl]-1-pyrrolidinecarboxylate.
Tert-Butyl (2R,3S)-3-hydroxy-2-[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]-1-pyrrolidinecarboxylate
NMR (CDCl3, xcex4): 1.41 (9H, m), 1.67-1.80 (3H, m), 2.63-4.18 (9H, m), 5.19 (1H, s), 6.87 (2H, m), 6.84-7.30 (16H, m)
MASS (APCI): 545 (M+1)
Preparation 72
To a solution of (4R,9aR)-8-acetyl-4-benzhydryl-2-(2-methoxybenzyl)octahydro-2H-pyrazino[1,2-a]pyrazine (5.9 g) in dichloroethane (60 ml) was added 1-chloroethyl chloroformate (2.3 ml) at room temperature, and the reaction mixture was heated at 70xc2x0 C. for 30 minutes with stirring. After removal of solvent by evaporation, to the resulting residue was added methanol (45 ml), and the solution was refluxed for 40 minutes. After being concentrated, the residue was triturated with diisopropyl ether. The resulting precipitate was collected by filtration and dried under, reduced pressure for 5 hours at 40xc2x0 C. to give (4R,9aR)-8-acetyl-4-benzhydryloctahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (3.1 g) as colorless foam.
NMR (DMSO-d6, xcex4): 1.90-2.00 (3H, m), 2.20-4.70 (13H, m), 7.10-7.50 (10H, m), 9.65 (2H, br)
MASS (APCI): 350 (M+H)+ (free)
Preparation 73
Under nitrogen atmosphere, to a solution of 5-bromo-2-methoxybenzaldehyde (350 mg) in dimethoxyethane (3.5 ml) were added 3-thiopheneboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (0) (282 mg), and 2M sodium carbonate (4.9 ml) at room temperature. After being heated at 80xc2x0 C. with stirring for 5 hours, the reaction mixture was poured into mixed solvents of ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (6 g) using a mixed solvent of hexane and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-methoxy-5-(3-thienyl)benzaldehyde (290 mg) as yellowish oil.
IR (Neat): 3103, 2941, 2854, 1682, 1610, 1495, 1255, 1174 cmxe2x88x921 
NMR (CDCl3, xcex4): 3.96 (3H, s), 7.03 (1H, d, J=8.7 Hz), 7.30-7.50 (3H, m), 7.79 (1H, dd, J=2.5 Hz, J=8.7 Hz), 8.06 (1H, d, J=2.5 Hz), 10.50 (1H, s)
MASS (APCI): 219 (M+H)+
Preparation 74
A solution of 1-fluoro-2-methyl-4-nitrobenzene (10 g) in methanol (200 ml) was hydrogenated over 10% palladium-charcoal (50% wet, 1.0 g) at room temperature under atmospheric pressure for 8 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give a syrup. The syrup was dissolved into dichloromethane (200 ml) and thereto triethylamine (16.2 ml) and trifluroacetic anhydride (14.9 g) were added dropwise. The whole mixture was stirred for 5 hours at room temperature and then washed with water and brine successively. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure to give 2,2,2-trifluoro-N-(4-fluoro-3-methylphenyl)acetamide (14.5 g).
NMR (CDCl3, xcex4): 2.28 (3H, d, J=2.0 Hz), 6.96-7.05 (1H, m), 7.31-7.46 (1H, m), 8.09 (1H, br s)
MASS (APCI): 244 (M+Na)+
Preparation 75
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-methylphenyl)acetamide (14.3 g) and triphenylphosphine (19.5 g) in tetrachloromethane (140 ml) was stirred for 17 hours at 100xc2x0 C. An additional triphenylphosphine (5 g) was added to the mixture and the whole was stirred for 5 hours and finally triphenylphosphine (5 g) was added to the mixture, and the whole was stirred further for 15 hours at 100xc2x0 C. After being cooled to room temperature hexane was added to the reaction mixture and the whole was stirred for 0.5 hour under ice-cooling. The resulting precipitate was removed by filtration and washed with hexane. The combined filtrate and washing were evaporated under reduced pressure below 20xc2x0 C. A mixture of the syrup obtained and sodium azide (10.6 g) in acetic acid (100 ml) was stirred at room temperature for 7 hours, followed by at 70xc2x0 C. for 17 hours. After being cooled to room temperature, the mixture was poured into ice-water, and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (100:1-5:1). The fractions containing the objective compound were collected to give 1-(4-fluoro-3-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole (15.2 g) as a syrup.
NMR (CDCl3, xcex4): 2.40 (3H, d, J=2.0 Hz), 7.19-7.63 (3H, m)
MASS: 247 (M+H)+ 219
Preparation 76
2,2xe2x80x2-Azobis(4-methoxy-2,4-dimethylvaleronitrile) (50 mg) was added by three portions to the mixture of 1-(4-fluoro-3-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole and N-bromophtalimide (1.44 g) in dichloromethane (16 ml) at 30xc2x0 C. and the whole was stirred at reflux for 3 hours. After being cooled to room temperature, the mixture was washed with aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate successively. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure to give a crude 1-[3-(bromomethyl)-4-fluorophenyl]-5-(trifluoromethyl)-1H-tetrazole (3:7).
NMR (CDCl3, xcex4): 4.54 (2H, d, J=1.0 Hz), 7.19-7.63 (3H, m)
Preparation 77
To a solution of (2S)-2-ethoxycarbonylpiperazine-1-carboxylic acid 1-tert-butyl ester D-tartarate (9.56 g) in tetrahydrofuran (90 ml) and water (90 ml) was added sodium bicarbonate (7.87 g) under ice-cooling. Benzyl chloroformate (4.01 ml) was added dropwise to the solution over 2 minutes at the same temperature, and stirred at room temperature for 15 minutes. Ethyl acetate (60 ml) and sodium chloride (5 g) was added to the mixture. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give (2S)-2-ethoxycarbonylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (10.4 g) as a colorless oil.
NMR (CDCl3, xcex4): 1.10-1.60 (12H, m), 2.60-4.80 (9H, m), 5.00-5.30 (2H, m), 7.20-7.40 (5H, m)
MASS (API-ES): 415 (M+Na)+
Preparation 78
Under nitrogen atmosphere, to a solution of (2S)-2-ethoxycarbonylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (9.35 g) was added portionwise lithium borohydride (1.82 g), and the reaction mixture was stirred for 90 minutes. After methanol (2.32 ml) was added dropwise to the solution under ice-cooling, the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid (80 ml) was added dropwise under ice-cooling, and ethyl acetate (100 ml) and sodium chloride (6 g) was added to it. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give colorless oil. The oil was purified by column chromatography on silica gel (90 g) using a mixed solvent of hexane and ethyl acetate (3:2). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (8.40 g) as a colorless oil.
NMR (CDCl3, xcex4): 1.46 (9H, s), 2.40-4.30 (10H, m), 5.10-5.30 (2H, m), 7.30-7.50 (5H, m)
MASS (API-ES): 373 (M+Na)+
Preparation 79
Under nitrogen atmosphere, to a solution of oxalyl chloride (1.64 ml) in dichloromethane (34 ml) under xe2x88x9265xc2x0 C., was added dropwise a solution of dimethyl sulfoxide (2.0 ml) in dichloromethane (15 ml) and stirred for 10 minutes at the same temperature. A solution of (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.29 g) in dichloromethane (24 ml) was dropped into the above solution over 5 minutes under xe2x88x9265xc2x0 C. The reaction mixture was stirred at the same temperature for 15 minutes, then stirred at xe2x88x9245xc2x0 C. for 90 minutes. Triethylamine (7.85 ml) was added to the solution under xe2x88x9240xc2x0 C., and the mixture was stirred at 0xc2x0 C. for 20 minutes. The mixture was poured into saturated aqueous ammonium chloride (100 ml). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.33 g) as a colorless syrup.
NMR (CDCl3, xcex4): 1.40-1.70 (9H, m), 2.85-3.30 (3H, m), 3.70-4.80 (4H, m), 5.05-5.30 (2H, m), 7.30-7.40 (5H, m), 9.58 (1H, s)
MASS (API-ES): 371 (M+Na)+
Preparation 80
A solution of 3-bromo-1,1-diphenyl-2-propanone (0.5 g) in tetrahydrofuran (10 ml) was added to a mixture of (2-methoxy-benzyl)amine (1.13 ml) and N,N-diisopropylethylamine (0.602 ml) in tetrahydrofuran (12 ml) over 0.5 hour at room temperature. After being stirred at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure to half volume and the resulting mixture was poured into ice-water (10 ml) and extracted with ethyl acetate (10 mlxc3x972). The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-[(2-methoxybenzyl)amino]-1,1-diphenylpropan-2-one (483 mg) as a colourless syrup.
NMR (CDCl3, xcex4): 3.63 (2H, s), 3.73 (2H, s), 3.79 (3H, s), 5.13 (1H, s), 6.82-7.36 (14H, m)
MASS (APCI): 346 (M+H)+
Preparation 81
Under nitrogen atmosphere, to a solution of (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (2.64 g) and 3-(2-methoxybenzylamino)-1,1-diphenylpropan-2-one (3.66 g) in dichloromethane (30 ml) was added acetic acid (0.607 ml) and sodium tritacetoxyborohydride (4.82 g) under ice-cooling, and then it was stirred at room temperature for 3 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate (100 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (82 g) using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.24 g) as a syrup.
NMR (CDCl3, xcex4): 1.40-1.65 (9H, m), 2.65-5.40 (19H, m), 6.70-7.40 (19H, m)
MASS (APCI): 678 (M+H)+
Preparation 82
The following compound was obtained according to a similar manner for Preparation 72.
(4R,9aS)-4-Benzhydryl-8-(benzyloxycarbonyl)octahydro-2H-pyrazino-[1,2-a]pyrazine dihydrochloride
NMR (DMSO-d6, xcex4): 2.20-5.00 (13H, m), 5.07 (2H, s), 7.15-7.45 (15H, m), 9.53 (2H, br)
MASS (APCI): 442 (M+H)+ (free)
Preparation 83
The following compound was obtained according to a similar manner to that of Preparation 34.
Benzyl [1-(N-methoxy-N-methylcarbamoyl)cyclopentyl]carbamate
NMR (CDCl3, xcex4): 1.61-1.74 (4H, m), 1.86-2.00 (2H, m), 2.22-2.40 (2H, m), 3.13 (3H, s), 3.53 (3H,. s), 5.07 (1H, br s), 5.10 (2H, s), 7.29-7.35 (5H, m)
MASS (APCI): 635 (2M+Na), 329 (M+Na)+
Preparation 84
The following compounds were obtained according to a similar manner to that of Preparation 35.
(1) Benzyl (1-formylcyclopentyl)carbamate
NMR (CDCl3, xcex4): 1.61-2.17 (8H, m), 5.10 (2H, s), 5.26 (1H, br s), 7.29-7.35 (5H, m), 9.53 (1H, s)
MASS (APCI): 204, 248 (M+H)+
(2) Benzyl [1-[(benzylamino)methyl]cyclopentyl]carbamate
NMR (CDCl3, xcex4): 1.50-2.04 (9H, m), 2.76 (2H, s), 3.79 (2H, s), 5.05 (2H, s), 5.18 (1H, br s), 7.20-7.35 (10H, m)
MASS (APCI): 339 (M+H)+, 231
(3) Benzyl [1-[[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]cyclopentyl]carbamate
NMR (CDCl3, xcex4): 1.50-2.04 (8H, m), 2.92 (2H, s), 3.48 (2H, s), 3.75 (2H, s), 4.90-5.00 (4H, s), 7.20-7.35 (20H, m)
MASS (APCI): 547 (M+H)+, 406
Preparation 85
The following compound was obtained according to a similar manner to that of Preparation 18.
7-Benzhydryl-6,9-diazaspiro[4.5]decane
MASS (APCI): 307 (M+H)+ (free)
Preparation 86
The following compound was obtained according to a similar manner to that of Preparation 35.
Benzyl [2-(benzylamino)-1,1-dimethylethyl]carbamate
NMR (CDCl3, xcex4): 1.28 (6H, s), 2.63 (1H, s), 3.81 (2H, s), 3.79 (2H, s), 5.04 (2H, s), 5.42 (1H, br s), 7.20-7.35 (10H, m)
MASS (APCI): 313 (M+H)+
Preparation 87
The following compound was obtained according to a similar manner to that of Preparation 17.
Benzyl [2-[N-benzyl-N-(2-oxo-3,3-iphenylpropyl)amino]-1,1-dimethylethyl]carbamate
NMR (CDCl3, xcex4) 1.28 (6H, s), 2.77 (2H, s), 3.53 (2H, s), 3.78 (2H, s), 5.00 (2H, s), 5.44 (1H, br s), 7.20-7.35 (20H, m)
MASS (APCI): 521 (M+H)+, 413
Preparation 88
The following compound was obtained according to a similar manner to that of Preparation 18.
6-Benzhydryl-2,2-dimethylpiperazine
IR (KBr): 3400, 1648, 1504 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.96 (3H, s), 1.29 (3H, s), 2.28-2.39 (1H, m), 2.53 (1H, d, J=12.2 Hz), 2.60 (1H, d, J=12.2 Hz), 2.72 (1H, d, J=11.0 Hz), 3.62-3.74 (2H, m), 7.14-7.38 (10H, m)
MASS (APCI): 281 (M+H)+ (free)
Preparation 89
The following compound was obtained according to a similar manner to that of Example 4.
2-[2-Benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-piperazinyl]acetic acid
MASS (APCI): 567 (M+H)+
Dihydrochloride of the above compound
IR (KBr, FT-IR): 1615, 1440, 1320, 1265, 1235 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.70-5.15 (12H, m), 3.84 (3H, s), 7.10-8.10 (13H, m), 10.36 (1H, br s)
MASS (APCI): 567 (M+H)+ (free)
Preparation 90
Sodium triacetoxyborohydride (163 mg) was added to a mixture of bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (0.38 g) and 2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzaldehyde (210 mg) in dichloromethane, and the whole was stirred for 3 hours at room temperature. The mixture was washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The later eluting fractions were collected and evaporated under reduced pressure to give colorless oil of (4R,7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-octahydropyrrolo[1,2-a]pyrazine (0.18 g).
NMR (CDCl3, xcex4): xe2x88x920.20 (3H, s), xe2x88x920.11 (3H, m), 0.75 (9H, m), 1.58-1.74 (4H, m), 2.18 (1H, dd, J=4.7 and 9.6 Hz), 2.26 (1H, dd, J=3.3 and 11.3 Hz), 2.31 (1H, d, J =11.3 Hz), 2.69 (1H, dd, J=3.0 and 10.6 Hz), 2.96 (1H, dd, J=6.7 and 9.5 Hz), 3.25 (1H, d, J=14.8 Hz), 3.30-3.50 (1H, m), 3.69 (1H, d, J=10.6 Hz), 3.87 (3H, s), 4.20-4.25 (1H, m), 4.66 (1H, d, J=10.8 Hz), 6.94-7.40 (12H, m), 7.54 (1H, d, J=2.6 Hz)
MASS (APCI-ES): 679 (M+H)+
The earlier eluting fractions were collected and evaporated under reduced pressure to give colorless oil of (4S,7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazine (0.15 g).
NMR (CDCl3, xcex4): xe2x88x920.20 (3H, s), xe2x88x920.11 (3H, m), 0.75 (9H, m), 1.56-1.95 (6H, m), 2.47 (1H, d, J=11.2 Hz), 2.64-2.92 (2H, m), 3.36-3.60 (3H, m), 2.78 (3H, s), 3.92 (1H, d, J=11.1 Hz), 4.07-4.17 (1H, m), 6.92 (1H, d, J=8.8 Hz), 7.05-7.45 (12H, m)
MASS (APCI-ES): 679 (M+H)+ (free)
Preparation 91
The following compound was obtained according to a similar manner to that of Preparation 56 from (4R,8S,8aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazin-8-ol.
(4R,8R,8aR)-8-Azido-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazine
MASS (APCI): 590 (M+1)
Preparation 92
The following compound was obtained according to a similar manner to that of Preparation 64 from (4R,8S,8aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazin-8-ol.
(4R,8R,8aR)-4-Benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazin-8-yl acetate
NMR (CDCl3, xcex4): 1.91-2.23 (5H, m), 2.03 (3H, s), 2.43 (2H, br), 2.63-2.89 (2H, m), 3.24 (1H, br), 3.42-3.64 (2H, dxc3x972, J=15 Hz), 3.78 (3H, s), 4.09 (1H, m), 5.18 (1H, m), 6.90-7.42 (13H, m)
MASS (APCI): 607 (M+1)
Preparation 93
The following compound was obtained according to a similar manner to that of Preparation 56 from (4R,8R,8aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazin-8-ol.
(4R,8S,8aR)-8-Azido-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydropyrrolo[1,2-a]pyrazine
MASS (APCI): 590 (M+1) (free)
Preparation 94
To a mixture of (4R,9aS)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (80 mg), cyclopentanecarboxylic acid (16.9 xcexcl), 1-hydroxybenzotriazole hydrate (23 mg), and triethylamine (79 xcexcl) in dichloromethane (1 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride at room temperature. After stirring at room temperature overnight, the mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with preparative TLC (methanol/chloroform=1/9) to give an oil. To a solution of the oil in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (0.2 ml) and hexane (20 ml). After stirring for 30 minutes, the precipitate was collected by filtration and dried under reduced pressure at 50xc2x0 C. for 5 hours to give (4R,9aR)-4-benzhydryl-8-cyclopentanecarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (63.9 mg) as a powder.
mp: 170-178xc2x0 C., decomp.
[xcex1]D27: xe2x88x9237.83 (C, 0.115, MeOH)
IR (KBr) 1647 cmxe2x88x921 
NMR (DMSO-d6, xcex4) 1.40-1.80 (8H, m), 2.20-4.50 (16H, m), 3.80 and 3.82 (total 3H, s), 7.15-7.82 (13H, m)
MASS (APCI+): 660.2 (MH+) (free)